Streptococcus mutans is the primary etiological agent of dental caries, a costly and ubiquitous health problem worldwide. The ability of this organism to cause disease depends on its abilities to adhere to the tooth surface, form tenacious biofilms and tolerate acid and other detrimental conditions in the oral cavity. We previously showed that the biofilm regulatory protein A (BrpA) plays a major role in regulation of acid- and oxidative-stress tolerance and biofilm formation in S. mutans. Deficiency of BrpA dramatically increased the susceptibility of the deficient mutants to acid-killing and hydrogen peroxide challenge. The BrpA-deficient mutant was able to bind to and form microcolonies on a surface, but failed to accumulate and develop mature biofilms. Predicted as a surface-associated protein, BrpA is a glycoprotein and possesses compositional and structural features that appear to be unique to S. mutans in the oral flora. Therefore, BrpA has great potential as a candidate for drug and vaccine production that may eliminate S. mutans from the plaque without disrupting other beneficial microorganisms in the flora. This study is designed to further investigate BrpA in regards to the (i) cellular location and structure-function relationships, (ii) regulation of expression in response to environmental stimuli, and (iii) role in the adherence, persistence and competitiveness of S. mutans when grown in mixed-species biofilms. The information derived from this study will contribute to a better understanding of the role and the underlying mechanism of BrpA in regulation of S. mutans pathogenicity and will enrich our knowledge on the ecology of the oral flora. More importantly, the data derived from this study could facilitate the design of therapeutic and preventive strategies to combat dental caries and possibly infective endocarditis. PUBLIC HEALTH RELEVANCE: The ability of Streptococcus mutans to cause dental caries depends on its ability to adhere to and form tenacious biofilms on the tooth surface and to tolerate detrimental conditions in the oral cavity. Glycoprotein BrpA in S. mutans plays major roles in environmental stress tolerance and formation of biofilms. This study will further investigate the role and the underlying mechanisms of BrpA in regulation of S. mutans pathogenicity and the potential for targeting BrpA in anti-caries strategy.